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419 Intramuscular immunization with rVCG-MECA vaccine elicits stronger chlamydial specific immune response than intranasal immunization 419 与鼻内免疫相比,肌肉注射 rVCG-MECA 疫苗可引起更强的衣原体特异性免疫反应
IF 2.6 Q3 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2024-04-03 DOI: 10.1017/cts.2024.363
Medhavi FNU, Tanner Tayhlor, Richardson Shakyra, Jones Leandra, Bell Counrtnee, Josesph U. Igietseme, Omosun Yusuf, Eko Francis
OBJECTIVES/GOALS: We prioritize Chlamydia’s public health impact, aim to develop rVCG-MECA for practical use, study robust immunity for effective strategies, and assess animal models for human vaccination adaptation. Our work highlights rVCG-MECA’s translational significance in public health. METHODS/STUDY POPULATION: Female Mice C57BL/6J mice (N=8) were immunized intramuscularly(IM) and intranasally(IN) and boosted twice, two weeks apart, with rVCG-MECA, once with live Chlamydia (C. trachomatis serovar D elementary bodies) and PBS. Specific mucosal and systemic immune responses were characterized. Vaccine efficacy was determined from chlamydia shedding following the transcervical challenge. Additionally, Chlamydia-specific cytokine (IFN-γ and IL-4) production by splenic and ILN T cells was assessed after 16 weeks RESULTS/ANTICIPATED RESULTS: Immunization with rVCG-MECA via intramuscular and intranasal routes triggered notable humoral responses in systemic and mucosal tissues. Intramuscular vaccination produced higher IgG2c levels in both tissues, while intranasal vaccination led to elevated IgA levels in mucosal tissues. rVCG-MECA-immunized mice exhibited significantly higher IFN-γ (Th1) secretion compared to IL-4 (Th2), with intramuscular immunization showing the highest IFN-γ levels. These findings anticipate robust immune responses, promising protection against Chlamydia, particularly through the intra muscular route. Overall, our results support rVCG-MECA as a promising Chlamydia vaccine, aligned with public health goals. DISCUSSION/SIGNIFICANCE: This study suggests that IM and IN immunization with rVCG-MECA induces immune effectors such as IFN-gamma and IgG2c that mediate chlamydial clearance in the genetical tract.
目标/目的:我们优先考虑衣原体对公共卫生的影响,旨在开发可实际使用的 rVCG-MECA,研究强免疫力以制定有效策略,并评估动物模型以适应人类疫苗接种。我们的工作凸显了 rVCG-MECA 在公共卫生领域的转化意义。方法/研究人群:对雌性 C57BL/6J 小鼠(N=8)进行肌肉注射(IM)和鼻内注射(IN),并用 rVCG-MECA 增强免疫两次,每次间隔两周,一次用活衣原体(沙眼衣原体血清 D 原体),另一次用 PBS。对特异性粘膜和全身免疫反应进行了鉴定。根据经宫颈挑战后的衣原体脱落情况确定疫苗的有效性。此外,16 周后还评估了脾脏和 ILN T 细胞产生的衣原体特异性细胞因子(IFN-γ 和 IL-4) 结果/预期结果:通过肌肉注射和鼻内途径接种 rVCG-MECA 可在全身和粘膜组织中引发显著的体液反应。rVCG-MECA免疫小鼠的IFN-γ(Th1)分泌量明显高于IL-4(Th2)分泌量,其中肌肉免疫的IFN-γ水平最高。这些发现预示着强大的免疫反应,有望保护人体免受衣原体感染,尤其是通过肌内途径。总之,我们的研究结果表明 rVCG-MECA 是一种有前途的衣原体疫苗,符合公共卫生目标。讨论/意义:这项研究表明,rVCG-MECA 的 IM 和 IN 免疫可诱导 IFN-gamma 和 IgG2c 等免疫效应因子,从而介导基因道中的衣原体清除。
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引用次数: 0
504 Dihydroxyacetone, a combustion of electronic cigarettes, promotes cardiac-specific injury through metabolic and mitochondrial imbalances 504 电子香烟燃烧物二羟基丙酮通过新陈代谢和线粒体失衡促进心脏特异性损伤
IF 2.6 Q3 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2024-04-03 DOI: 10.1017/cts.2024.428
Arlet Hernandez, M Gwin, LA Wiggins, H Bryant, M Vasilyev, VL Dal Zotto, ML Bates, M Schuler, NR Gassman
OBJECTIVES/GOALS: Electronic cigarettes have become increasingly popular, with various combustion products generated in the process. Dihydroxyacetone (DHA), a carbohydrate made during the heating process. Exposures may reach high micromolar to low millimolar doses of DHA per day and no studies have been done to understand the effects of DHA in the heart. METHODS/STUDY POPULATION: Here, we examine if DHA contributes to these using rat cardiomyocytes, H9c2 cells, and rat cardiac tissues to DHA evaluating metabolic and mitochondrial effects. Using the cells, we will investigate metabolic and mitochondrial pathways using Seahorse, protein expression changes in nutrient sensing pathways, and understand dose-dependent effects of DHA in the heart. Metabolite pools will also be evaluated to understand the changes promoted by DHA. Oxidative stress as previously observed in other cell models will also be measured. Key findings in the cardiac cells will be investigated in the cardiac tissues exposed to DHA. RESULTS/ANTICIPATED RESULTS: We have previously shown DHA induces oxidative stress, metabolic changes, and mitochondrial dysfunction in various cell line models. Interestingly, these effects are highly cell-type dependent. E-cigarettes are known to have toxic cardiac effects, including arterial stiffness, endothelial dysfunction, vascular injury, and oxidative stress. Changes in glycolytic, fatty acid synthesis, and the citric acid cycle enzymes and metabolites were found in the H9c2 cells. We also observed increased mitochondrial ROS and fuel changes due to DHA exposure. In DHA exposed cardiac tissues, we observed oxidative stress and mitochondrial fission and fusion dynamics altered. DISCUSSION/SIGNIFICANCE: These data suggest further study at physiologically relevant doses is warranted to understand how DHA inhaled impacts the long-term health of vapers. As well as the regulation of DHA in e-cigarettes as it has been deemed as safe for topical applications and warned against inhalation.
目的/目标:电子香烟越来越受欢迎,在使用过程中会产生各种燃烧产物。二羟基丙酮(DHA)是加热过程中产生的一种碳水化合物。每天接触的 DHA 剂量可能从高微摩尔到低毫摩尔不等,目前还没有研究了解 DHA 对心脏的影响。方法/研究人群:在此,我们将使用大鼠心肌细胞、H9c2 细胞和大鼠心脏组织来研究 DHA 是否会对代谢和线粒体效应产生影响。利用这些细胞,我们将使用海马研究代谢和线粒体途径、营养传感途径中的蛋白质表达变化,并了解 DHA 在心脏中的剂量依赖性效应。还将对代谢物池进行评估,以了解 DHA 促进的变化。还将测量之前在其他细胞模型中观察到的氧化应激。心脏细胞中的主要发现将在暴露于 DHA 的心脏组织中进行研究。结果/预期结果:我们以前曾在各种细胞系模型中发现 DHA 会诱导氧化应激、新陈代谢变化和线粒体功能障碍。有趣的是,这些影响高度依赖于细胞类型。众所周知,电子烟具有毒性心脏效应,包括动脉僵化、内皮功能障碍、血管损伤和氧化应激。在 H9c2 细胞中发现了糖酵解、脂肪酸合成、柠檬酸循环酶和代谢物的变化。我们还观察到线粒体 ROS 的增加以及 DHA 暴露导致的燃料变化。在暴露于 DHA 的心脏组织中,我们观察到氧化应激和线粒体裂变与融合动力学发生了改变。讨论/意义:这些数据表明,有必要对生理相关剂量进行进一步研究,以了解吸入的 DHA 如何影响吸食者的长期健康。以及对电子烟中 DHA 的监管,因为 DHA 被认为对局部应用是安全的,但警告不要吸入。
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引用次数: 0
441 Transcriptomic analysis of Influenza A infected lung organoids reveals Warburg-like phenotype 441 甲型流感感染肺器官组织的转录组分析揭示了沃伯格样表型
IF 2.6 Q3 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2024-04-03 DOI: 10.1017/cts.2024.379
Emily Hartsell, Justin T. Roberts, Adeyeye I. Haastrup, Raymond J. Langley
OBJECTIVES/GOALS: The CDC estimates that Influenza infections account for an average of 420,000 hospitalizations and 34,700 deaths in the U.S. each year. This project explores the underlying mechanisms of the infectious process of Influenza A in human lung organoids by examining the differential transcriptomic expression compared to uninfected controls. METHODS/STUDY POPULATION: Lung organoids were cultured from differentiated human bronchial epithelial cells from lung transplant donors on an air-liquid interface until they were confirmed to contain both mucous producing and ciliated cells. Lung organoids are ideal models in translational science due to their structural and functional characteristics which closely mimic those of in vivo human epithelial tissue. Half the organoids were exposed to Influenza A pH1N1 for 72h; the other half served as uninfected controls. RNA was isolated from both groups and sequenced using the Oxford Nanopore MinION which generates full length reads. Reads were aligned to the human reference genome (GRCh38.p14) using Minimap2. RESULTS/ANTICIPATED RESULTS: The MinION sequenced an average of 3.24m reads per sample and a total of 13,128 genes were relevantly expressed (defined as greater than 1 read per million in at least half the samples). ANOVA with a 5% false discovery rate (Benjamini and Hochberg correction) revealed 5,417 differentially expressed genes between infected and control groups. Within this subset, we identified downregulation of mucociliary clearance, mitochondrial and ß-oxidation, peroxisome, and glutathione replenishment genes. We further identified upregulation in inflammatory markers, lactate dehydrogenase enzymes, and several s100 proteins. The downregulation of mitochondrial and β-oxidation markers and the upregulation of lactate dehydrogenase enzymes revealed a Warburg-like phenotype which has not previously been reported. DISCUSSION/SIGNIFICANCE: This study reveals a novel Warburg-like phenotype in Influenza A infection alongside downregulated mucociliary clearance and upregulated inflammatory processes. These findings improve our understanding of Influenza A infection and point to potential therapeutic targets to advance precision medicine approaches to treatment.
目的/目标:据美国疾病预防控制中心(CDC)估计,美国每年平均有 420,000 人因感染流感而住院,34,700 人因感染流感而死亡。本项目通过研究与未感染对照组相比的转录组表达差异,探索甲型流感在人肺器官组织中感染过程的潜在机制。方法/研究人群:肺器官组织由肺移植供体分化出的人类支气管上皮细胞在空气-液体界面上培养而成,直至确认其中含有粘液分泌细胞和纤毛细胞。肺器官组织是转化科学的理想模型,因为其结构和功能特征与体内人体上皮组织非常相似。一半的有机体暴露于甲型 pH1N1 流感病毒 72 小时,另一半作为未感染的对照组。从两组组织中分离出 RNA,并使用牛津纳米孔 MinION 测序仪对其进行测序。使用 Minimap2 将读数与人类参考基因组 (GRCh38.p14) 进行比对。结果/相关结果:MinION 对每个样本平均测序 324 万个读数,共有 13 128 个基因有相关表达(定义为至少一半样本中的读数大于百万分之一)。采用方差分析和 5%的误发现率(Benjamini 和 Hochberg 校正)发现,感染组和对照组之间有 5417 个差异表达基因。在这个子集中,我们发现了粘膜清除、线粒体和氧化、过氧化物酶体和谷胱甘肽补充基因的下调。我们进一步确定了炎症标志物、乳酸脱氢酶和几种 s100 蛋白的上调。线粒体和β-氧化标志物的下调以及乳酸脱氢酶的上调揭示了一种沃伯格样表型,这是以前从未报道过的。讨论/意义:本研究揭示了甲型流感感染中的一种新型沃伯格样表型,同时还发现了下调的黏膜纤毛清除率和上调的炎症过程。这些发现增进了我们对甲型流感感染的了解,并指出了潜在的治疗靶点,从而推动了精准医学治疗方法的发展。
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引用次数: 0
324 An umbrella protocol that establishes an enterprise-wide framework for the operation of a Clinical Data Warehouse 324 为临床数据仓库的运行建立全企业框架的总协议
IF 2.6 Q3 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2024-04-03 DOI: 10.1017/cts.2024.294
Daniella Garofalo, Allison Orechwa, Neil Bahroos
OBJECTIVES/GOALS: To streamline the standards and procedures for operating a research-specific, clinical data warehouse, acheived by defining roles, introducing a common language, and categorizing dataset types to provide transparency regarding data security risks inherent in the use of patient data. METHODS/STUDY POPULATION: We established a Bioethics committee responsible for ensuring clinical data is securely procured, maintained, and extracted in a manner that adheres to all federal, state, and local laws. We created an operational framework in the form of an umbrella IRB protocol and shared it with the bioethics committee for feedback and approval. The protocol was approved first by the bioethics committee and subsequently by the IRB. It was then disseminated across the institution and published online for continuous reference and use by committee members, researchers, and the data warehouse service team. RESULTS/ANTICIPATED RESULTS: The resulting framework defined the roles of researchers, data warehouse service team members, and honest brokers; explains the procedures for accessing and securely delivering data; and lists six categories of datasets according to type and implicit risks: datasets that are preparatory for research/aggregate counts, anonymized datasets, coded datasets, limited datasets, identified datasets for recruitment purposes, and defined identified cohort datasets. The protocol is approved and in use enterprise-wide, has reduced the number of questions from stakeholders, and has given researchers, IRB members, and informatics staff confidence in the use of the clinical research data warehouse. DISCUSSION/SIGNIFICANCE: We offer our framework to CTSAs interested in streamlining their data warehouse operations. We believe the adoption of this framework will establish strong procedures for ensuring compliance with IRB requirements, data privacy, and data security while reducing barriers to clinical research.
目的/目标:通过定义角色、引入通用语言以及对数据集类型进行分类,简化针对特定研究的临床数据仓库的操作标准和程序,从而使患者数据使用过程中固有的数据安全风险透明化。方法/研究对象:我们成立了一个生物伦理委员会,负责确保临床数据的安全采购、维护和提取符合所有联邦、州和地方法律。我们以总体 IRB 协议的形式创建了一个操作框架,并与生物伦理委员会共享,以获得反馈和批准。该协议首先获得了生物伦理委员会的批准,随后又获得了 IRB 的批准。随后,该协议在整个机构内传播,并在网上发布,供委员会成员、研究人员和数据仓库服务团队持续参考和使用。结果/预期结果:由此产生的框架界定了研究人员、数据仓库服务团队成员和诚信经纪人的角色;解释了访问和安全交付数据的程序;并根据类型和隐含风险列出了六类数据集:准备研究的数据集/汇总计数、匿名数据集、编码数据集、有限数据集、用于招募目的的已识别数据集和已定义的已识别队列数据集。该协议已获批准并在整个企业范围内使用,减少了利益相关者提出的问题数量,并使研究人员、IRB 成员和信息学人员对临床研究数据仓库的使用充满信心。讨论/意义:我们向有意简化数据仓库操作的临床研究机构提供了我们的框架。我们相信,采用该框架将建立强有力的程序,确保符合 IRB 要求、数据隐私和数据安全,同时减少临床研究的障碍。
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引用次数: 0
213 Accelerating Translational Science Through Dissemination Grants with Community Impact 213 通过具有社区影响力的传播补助金加速转化科学的发展
IF 2.6 Q3 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2024-04-03 DOI: 10.1017/cts.2024.201
Polly Gipson Allen, Tricia Piechowski, Sarah Bailey, Erica E. Marsh

OBJECTIVES/GOALS: Promoting Academics and Community Engagement (PACE) Dissemination grants are funding opportunities via the Michigan Institute for Clinical and Health Research Community Engagement program designed to support the science of clinical and translational research demonstrating community impact. METHODS/STUDY POPULATION: Two statewide funding announcements over a 3-month period were issued to over 2,000 academic and community partners. Proposals were required to meet the following criteria: 1) data collection from an academic and community partnered research project completed; 2) research findings analyzed; and 3) a community-focused dissemination plan developed. Projects were funded up to $5000. RESULTS/ANTICIPATED RESULTS: Six PACE dissemination grants with community-focused plans were funded spanning Southeast, Western, and the Upper Peninsula regions of Michigan, as well as statewide. Examples of funded projects topics areas include the following: firearm safety; housing discrimination; opioid misuse; suicide prevention; and youth mental health. Community dissemination activities include: a) presenting at a community town hall; b) writing a pamphlet for community use; c) creating artwork installation showcase for community display; d) storytelling through community channels; and e) designing and implementing a local social media campaign. DISCUSSION/SIGNIFICANCE: Traditional funding mechanisms often do not provide resources to disseminate research findings with community benefit or impact back to communities. Funding dissemination awards through the PACE mechanism directly supports and accelerates translational science by sharing results directly back to the community in meaningful ways.

目的/目标:促进学术和社区参与 (PACE) 传播补助金是密歇根临床和健康研究所社区参与计划提供的资助机会,旨在支持临床和转化研究科学对社区的影响。方法/研究对象:向 2,000 多名学术和社区合作伙伴发布了两个为期 3 个月的全州资助公告。提案必须符合以下标准:1) 完成学术和社区合作研究项目的数据收集;2) 分析研究结果;3) 制定以社区为重点的传播计划。项目最高可获得 5000 美元的资助。结果/预期结果:密歇根州东南部、西部和上半岛地区以及全州共资助了六项以社区为重点的 PACE 传播计划。获得资助的项目主题领域包括:枪支安全、住房歧视、阿片类药物滥用、自杀预防和青少年心理健康。社区传播活动包括:a) 在社区市政厅发表演讲;b) 编写供社区使用的小册子;c) 制作供社区展示的艺术品装置;d) 通过社区渠道讲故事;以及 e) 设计并实施本地社交媒体活动。讨论/意义:传统的资助机制往往无法提供资源,用于传播有益于社区或对社区有影响的研 究结果。通过 "计算机设备行动伙伴关系"(PACE)机制资助传播奖,以有意义的方式将成果直接反馈给社区,从而直接支持和加速转化科学。
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引用次数: 0
200 Assessing Pre-Diabetes Knowledge, Attitudes, & Needs: A Study of the CHW Translational Advisory Board of South Texas 200 评估糖尿病前期知识、态度和需求:对南得克萨斯州保健工作者转化咨询委员会的研究
IF 2.6 Q3 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2024-04-03 DOI: 10.1017/cts.2024.191
Elisabeth de la Rosa, Paula Winkler, Ariel Gomez, Belinda Flores, Ludivina Hernandez, Sharon Elwin, Virginia Lopez, April Kneuper, Vanessa Ortiz, Martha Flores, Raquel Romero, Kathryn E. Kanzler, The Community Health Worker Translational Advisory Board (TAB)

OBJECTIVES/GOALS: The CHW TAB is exploring pre-diabetes knowledge and perceived needs in south Texas to facilitate the role of CHWs to increase the capacity of community members to better manage their prediabetes diabetes risk. The long-term goal of this project is to show how the diagnosis of pre-diabetes can be managed to prevent type 2 diabetes. METHODS/STUDY POPULATION: We selected a two-pronged approach to gather quantitative and qualitative data. CHW TAB members collected data participated in different aspects of the project (e.g., study design, survey development, etc.). Data collection procedures include Quantitative - a 9-item survey in English and Spanish administered by each participating CHW in 2022 at community events. One hundred surveys were collected. In Phase 2: Qualitative, participants attended focus groups to gather in-depth data about pre-diabetes management, including challenges and opportunities, which will inform CHW-led intervention development. Eight English and one Spanish focus groups, with 65 participants in 6 counties were completed. RESULTS/ANTICIPATED RESULTS: This project is still in progress. Preliminary results show that most survey participants identify as Hispanic, and half have been diagnosed with pre-diabetes. Additionally, 87.8% report that prediabetes is a problem in their community. Preliminary focus group findings indicate that knowledge and support for managing prediabetes is missingin South Texas. Many participants report feeling “doomed” to develop type 2 diabetes but are eager to share their experiences. Additionally, participants report that family and culture play a huge part in their ability to eat healthier foods. DISCUSSION/SIGNIFICANCE: These findings can help identify knowledge gaps, strengths, and areas for promoting and empowering better health behaviors among those who have pre-diabetes. Participant feedback and focus group responses will inform a CHW-led educational intervention through our TAB.

目的/目标:社区保健工作者技术咨询委员会(CHW TAB)正在探索得克萨斯州南部的糖尿病前期知识和认知需求,以促进社区保健工作者发挥作用,提高社区成员更好地管理糖尿病前期风险的能力。该项目的长期目标是展示如何管理糖尿病前期诊断,以预防 2 型糖尿病。方法/研究人群:我们选择了一种双管齐下的方法来收集定量和定性数据。CHW TAB 成员在收集数据的过程中参与了项目的不同方面(如研究设计、调查开发等)。数据收集程序包括定量--2022 年,每位参与项目的社区保健工作者在社区活动中用英语和西班牙语进行 9 个项目的调查。共收集了 100 份调查问卷。第 2 阶段:定性--参与者参加焦点小组,收集有关糖尿病前期管理的深入数据,包括挑战和机遇,为社区保健工作者主导的干预措施开发提供信息。6 个县的 65 名参与者参加了 8 个英语焦点小组和 1 个西班牙语焦点小组。结果/预期结果:该项目仍在进行中。初步结果显示,大多数调查参与者都认为自己是西班牙裔,半数人被诊断为糖尿病前期。此外,87.8% 的人表示糖尿病是他们所在社区的一个问题。焦点小组的初步调查结果表明,南得克萨斯州缺乏管理糖尿病前期的知识和支持。许多参与者表示,他们感觉自己 "注定 "会患上 2 型糖尿病,但他们渴望分享自己的经验。此外,参与者还表示,家庭和文化对他们能否吃得更健康起到了很大的影响。讨论/意义:这些发现有助于找出知识差距、优势以及在糖尿病前期患者中推广和增强更好的健康行为的领域。参与者的反馈和焦点小组的回应将为我们的 TAB 开展由社区保健工作者主导的教育干预活动提供信息。
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引用次数: 0
178 Pace and Pitch: Predictive Factors for Seed Funding and Development 178 Pace and Pitch:种子基金和发展的预测因素
IF 2.6 Q3 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2024-04-03 DOI: 10.1017/cts.2024.169
Alyson Eggleston
OBJECTIVES/GOALS: Securing seed funding and external support can be a daunting process. Institutions are increasingly looks for quantitative assurance of impact and accountability. This study investigates factors predictive of seed funding selection, including pace of submissions as well as external support. METHODS/STUDY POPULATION: Using Generalized Logistic Mixed Models (GLMMs), we model factors found to be predictive of researcher success, and model demographic factors as well, to understand the complex interplay of researcher background, professional networks and preparation, and researcher persistence. The following factors were modeled as potentially predictive of researcher success: faculty rank; co-PI; h-index; rate of application; prior award funding amounts; and research-focused social media posts. RESULTS/ANTICIPATED RESULTS: After effects are finalized, we expect that pace of seed fund applications and the strength co-PIs, as measured by h-indices, to be significant predictors of researcher success for both securing seed funding and external support. DISCUSSION/SIGNIFICANCE: This study identifies features associated with eventual research program success and can be used to support accountability and impact efforts at an institutional level. Research institutes strive to ensure equal access to these opportunities and train applicants to produce improved project proposals. Results from this study inform these efforts.
目标/目的:获得种子资金和外部支持是一个艰巨的过程。越来越多的机构希望从数量上保证其影响力和责任感。本研究调查了种子基金选择的预测因素,包括提交申请的速度以及外部支持。方法/研究对象:我们使用广义逻辑混合模型(GLMMs)对研究人员成功的预测因素进行建模,并对人口统计因素进行建模,以了解研究人员背景、专业网络和准备工作以及研究人员持续性之间复杂的相互作用。以下因素被建模为研究人员成功的潜在预测因素:教师职级;共同第一作者;h 指数;申请率;之前的奖励资金数额;以及以研究为重点的社交媒体帖子。结果/预期结果:在最终确定效果后,我们预计种子基金申请速度和共同首席研究员的实力(以 h 指数衡量)将成为研究人员成功获得种子基金和外部支持的重要预测因素。讨论/意义:本研究确定了与研究项目最终成功相关的特征,可用于支持机构层面的问责和影响力工作。研究机构应努力确保平等获得这些机会,并对申请人进行培训,以改进项目提案。本研究的结果为这些工作提供了参考。
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引用次数: 0
358 In Vitro Uptake of Harmful Algal Bloom Toxin Microcystin-LR in Human Placental Cells 358 人类胎盘细胞对有害藻华毒素微囊藻毒素-LR 的体外吸收
IF 2.6 Q3 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2024-04-03 DOI: 10.1017/cts.2024.320
Michael Campbell, Mokshitkumar Patel, Shuo Xiao, Xia Wen, Lauren M. Aleksunes
OBJECTIVES/GOALS: Harmful algal blooms (HABs) are increasing in both frequency and intensity due to climate change. HABs release the toxin microcystin-LR (MC-LR) which enters cells via organic anion-transporting polypeptides (OATPs). In this study, we sought to assess the ability of MC-LR to accumulate in trophoblasts, potentially disrupting placental functions. METHODS/STUDY POPULATION: Intracellular accumulation of MC-LR at exposure concentrations of 0.1, 1, and 10 µM over 6 hrs was evaluated in immortalized JAR placental cytotrophoblasts. Western blotting was used to evaluate protein-bound MC-LR accumulation in JAR cells. The function of OATP transporters in JAR cells was determined by pre-incubating cells with 10µM cyclosporin A, a general OATP inhibitor for 1 hr, and then incubated with 1µM OATP substrate fluorescein for up to 40 min. Fluorescence of fluorescein was measured at Ex/Em: 494nm/515nm by spectrophotometry. RESULTS/ANTICIPATED RESULTS: A concentration-dependent increase of MC-LR bound proteins in JAR cells was observed at 6 hrs with the greatest intracellular accumulation of MC-LR at 10µM. In the transporter experiments, a significant decrease of fluorescein uptake by up to 45% into JAR cells was observed following cyclosporin A inhibition of OATPs. These findings are consistent with the functional expression of OATP transporters in JAR placenta cells. Ongoing studies are evaluating whether the cyclosporin A-mediated inhibition of OATPs also inhibits the uptake of MC-LR. DISCUSSION/SIGNIFICANCE: Although MC-LR is well-known for its hepatotoxic and neurotoxic effects, there is growing interest in examining its potential adverse impacts on female reproductive health, particularly during pregnancy. Active uptake of MC-LR into the placenta could interfere with placental and fetal development.
目标/目的:由于气候变化,有害藻华(HAB)的发生频率和强度都在增加。有害藻华释放的毒素微囊藻毒素-LR(MC-LR)通过有机阴离子转运多肽(OATPs)进入细胞。在本研究中,我们试图评估 MC-LR 在滋养细胞中的蓄积能力,这可能会破坏胎盘功能。方法/研究人群:在永生化的 JAR 胎盘滋养细胞中评估 MC-LR 在 0.1、1 和 10 µM 暴露浓度下 6 小时的细胞内蓄积。用 Western 印迹法评估 JAR 细胞中蛋白结合的 MC-LR 积累。在测定 JAR 细胞中 OATP 转运体的功能时,先用 10µM 环孢素 A(一种通用的 OATP 抑制剂)预孵育细胞 1 小时,然后用 1µM OATP 底物荧光素孵育细胞长达 40 分钟。用分光光度法在 Ex/Em: 494nm/515nm 处测量荧光素的荧光。结果/预期结果:6 小时后,观察到 JAR 细胞中与 MC-LR 结合的蛋白质呈浓度依赖性增加,10µM 时 MC-LR 在细胞内积累最多。在转运体实验中,观察到环孢素 A 抑制 OATPs 后,JAR 细胞对荧光素的摄取量显著减少了 45%。这些发现与 OATP 转运体在 JAR 胎盘细胞中的功能表达相一致。正在进行的研究正在评估环孢素 A 介导的 OATPs 抑制是否也会抑制 MC-LR 的摄取。讨论/意义:尽管 MC-LR 因其肝毒性和神经毒性作用而闻名,但人们越来越关注研究它对女性生殖健康的潜在不利影响,尤其是在怀孕期间。胎盘主动吸收 MC-LR 可能会影响胎盘和胎儿的发育。
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引用次数: 0
105 Gender-Diverse Inclusion: The Language of Sex and Gender in PrEP Clinical Trials 105 多性别包容:PrEP 临床试验中的性与性别语言
IF 2.6 Q3 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2024-04-03 DOI: 10.1017/cts.2024.103
Jeremiah Lee, Terry D. Church
OBJECTIVES/GOALS: To construct an assessment scale capable of evaluating a trial’s gender literacy or the extent to which biologically assigned “sex” is understood as separate from culturally defined and personally embodied “gender”. This scale in tandem with a policy brief will outline recommendations for inclusive medical nomenclature in the clinical space. METHODS/STUDY POPULATION: Using clinicaltrials.gov, inclusion/exclusion criteria was recorded for PrEP interventional trials (i.e., Truvada, Descovy). To evaluate these trials, an assessment scale for “gender literacy” is necessary. This scale relies on the fact that sex and gender are distinct elements to one’s identity and ought to be reported as such. As a form of content analysis, where literary information (eligibility criteria) is evaluated based on set rubric, this scale will require validation through inter-coder agreement. Evaluated in a group of 5 college-age students, this scale was used on selected PrEP clinical trials to verify if there was high agreement in the scores given. After validation, the dataset from clinicaltrials.gov underwent evaluation using the proposed assessment scale for gender literacy. RESULTS/ANTICIPATED RESULTS: The student coders had a Kalpha of 0.4 in the first round of grading. After retraining, their Kalpha increased to 0.68. The grading involved a subjective language rating (LIR), evaluating the usage of inclusive language, and a numerical score (GR) for the demographics of inclusion in a trial. After this inter-coder agreement validation, 216 active PrEP clinical trials (as of March 2023) were downloaded from clinicaltrials.gov. Grading of these trials showed that cisgender males represented 40% of participants, while 28% represented both transgender men and women, and less than 1% represented non-binary individuals. Moreover, more than half of the trials (52%) exhibited cisgender-oriented language or made no reference to gender identity. DISCUSSION/SIGNIFICANCE: It is a scientific imperative for clinical trials to have representative participant bases in order to derive data that is generalizable to afflicted populations. Especially for PrEP clinical trials, where gender-diverse individuals need visibility, trial design must be carefully crafted so as not to exclude through dated or exclusionary language.
目的/目标:构建一个评估量表,用于评估试验的性别素养,或生物分配的 "性别 "与文化定义和个人体现的 "性别 "在多大程度上是分开的。该量表将与一份政策简报一起,概述临床领域包容性医学术语的建议。方法/研究对象:使用 clinicaltrials.gov,记录 PrEP 干预试验(即 Truvada 和 Descovy)的纳入/排除标准。为了评估这些试验,有必要制定 "性别扫盲 "评估量表。该量表基于这样一个事实,即性和性别是一个人身份的不同要素,因此应该如实报告。作为内容分析的一种形式,文学信息(资格标准)根据设定的标准进行评估,该量表需要通过编码员之间的一致意见来验证。由 5 名大学生组成的小组对该量表进行了评估,并将其用于选定的 PrEP 临床试验,以验证给出的分数是否高度一致。经过验证后,使用建议的性别素养评估量表对来自 clinicaltrials.gov 的数据集进行了评估。结果/预期结果:在第一轮评分中,学生编码员的 Kalpha 值为 0.4。经过再培训后,他们的 Kalpha 值提高到了 0.68。评分包括主观语言评分 (LIR)(评估包容性语言的使用)和数字评分 (GR)(评估纳入试验的人口统计学特征)。在对编码员之间的一致意见进行验证后,从 clinicaltrials.gov 下载了 216 项有效的 PrEP 临床试验(截至 2023 年 3 月)。对这些试验的分级显示,顺性别男性占参与者的 40%,28% 的参与者既包括变性男性也包括变性女性,只有不到 1%的参与者是非二元个体。此外,半数以上的试验(52%)使用了以顺性性别为导向的语言或未提及性别认同。讨论/意义:临床试验必须要有代表性的参与者基础,这样才能获得对受影响人群具有普遍意义的数据。尤其是 PrEP 临床试验,因为需要关注不同性别的个体,所以必须精心设计试验设计,以免通过过时或排斥性的语言将其排除在外。
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引用次数: 0
564 Platelets and Leukocytes Interact to Modulate Inflammation in Patients with CKD 564 血小板和白细胞相互作用,调节慢性肾脏病患者的炎症反应
IF 2.6 Q3 MEDICINE, RESEARCH & EXPERIMENTAL Pub Date : 2024-04-03 DOI: 10.1017/cts.2024.480
Nishank Jain, Rajshekhar Kore, John M Arthur, Jerry Ware, Rupak Pathak
OBJECTIVES/GOALS: Platelets interact with leukocytes in the circulation to modulate inflammation in chronic diseases. In previous clinical study, we showed that platelet leukocyte interaction is reduced in the circulation of patients with CKD. Preclinical studies are needed to show whether these findings are a precursor to or a result of CKD. METHODS/STUDY POPULATION: We used mouse models (wild type and platelet-defect) and induced CKD with intraperitoneal cisplatin injections. We measured platelet leukocyte interactions before and after CKD induction in the two models. RESULTS/ANTICIPATED RESULTS: We found platelet-leukocyte interaction to reduce after CKD induction in both wild type and platelet-defect mice. This coincided with a pro-inflammatory state in these mice, as measured by serum TNFalpha levels. Specifically, pro-inflammatory state was exacerbated in CKD of mice with platelet-defects compared to the wild type. DISCUSSION/SIGNIFICANCE: These findings recapitulate translational findings in human CKD samples and confirm that CKD state results in reduced platelet-leukocyte interactions in the circulation, and this change imparts a pro-inflammatory state in the CKD state.
目的/目标:血小板与血液循环中的白细胞相互作用,调节慢性疾病的炎症反应。在之前的临床研究中,我们发现在慢性肾脏病患者的血液循环中,血小板与白细胞的相互作用减少。需要进行临床前研究,以证明这些发现是慢性肾脏病的前兆还是结果。方法/研究人群:我们使用小鼠模型(野生型和血小板缺陷型),并通过腹腔注射顺铂诱导 CKD。我们测量了两种模型在诱导 CKD 前后血小板与白细胞的相互作用。结果/预期结果:我们发现野生型小鼠和血小板缺陷小鼠在诱导 CKD 后血小板与白细胞的相互作用都有所减少。这与这些小鼠的促炎状态相吻合,以血清 TNFalpha 水平衡量。特别是,与野生型小鼠相比,血小板缺陷小鼠的促炎症状态在 CKD 中加剧。讨论/意义:这些研究结果再现了人类 CKD 样本中的转化发现,证实了 CKD 状态会导致循环中血小板-白细胞相互作用减少,而这种变化会在 CKD 状态下产生促炎状态。
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引用次数: 0
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Journal of Clinical and Translational Science
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